A customized regimen of intravitreal aflibercept for the treatment of choroidal neovascularization secondary to different chorioretinal diseases

Background To assess the response of CNV secondary to chorioretinal diseases to IVA and to explore the adequate dosing regimen and the long-term results. Methods A retrospective study including patients with treatment-naïve active CNV secondary to chorioretinal diseases. All patients received an initial IVA injection followed by a PRN regimen. The main outcome measures were improvement of BCVA, improvement of anatomical morphology and vascularity of the CNV on SS-OCT, and SS-OCTA, respectively, and ocular or systemic complications attributed to IVA. Results The study included 17 eyes of 15 patients. Nine patients (60%) were females. The median age was 20 years. The main primary chorioretinal disease was vitelliform macular dystrophy (29%). The mean baseline BCVA was 0.16. The mean follow-up period was 15 months. Final BCVA improved by a mean of 6 lines. The CNV regressed or became inactive in all eyes. The median number of IVA injections was 2. There were no ocular or systemic complications attributed to IVA. Conclusion The customized IVA regimen is effective in inducing long-term regression of secondary CNV and in improving BCVA. Multimodal imaging is fundamental in establishing the diagnosis of CNV, and in monitoring its response to IVA.


Background
The efficacy of intravitreal aflibercept (IVA) in treating neovascular age-related macular degeneration (nAMD) has been consolidated by landmark studies that demonstrated its non-inferiority to ranibizumab in terms of anatomical and visual outcomes [1][2][3]. The pharmacologic properties of aflibercept render it more avid than ranibizumab to vascular endothelial growth factor (VEGF) molecule. The resultant bondage with the VEGF molecule is stronger and more durable and enables instating a bi-monthly dosing regimen that is as effective as monthly ranibizumab but with less burden on the patient due to fewer injections delivered, the less cumulative risk of injection-related adverse events, and better quality of life [1,4,5]. Despite encouraging reports on the efficacy of IVA in choroidal neovascularization (CNV) secondary to pathologies other than nAMD, several aspects remain unexplained. While increased VEGF production is the common route on which different CNV-inciting pathologies converge, the response to anti-VEGF agents by CNV secondary to trauma, inflammation, and hereditary and degenerative disorders is not uniform and suggests that the VEGF load involved is largely modulated by the selflimited nature of the inciting pathology in contrast to the perpetual natural history of AMD [6][7][8]. Consequently, there is no consensus on the optimum initial dosing regimen and consecutive protocols for continuing treatment. This study aims to assess the response of CNV secondary to different fundus pathologies other than AMD to IVA and to explore the adequate dosing regimen and results of long-term follow-up.

Methods
This is a retrospective study including consecutive patients who received IVA for CNV secondary to different fundus pathologies between 2015 and 2021. The study was conducted in a retina tertiary center in Egypt. We diagnosed CNV based on clinical examination, fundus fluorescein angiography (FFA); Topcon TRC 50DX fundus camera (Topcon Corporation, Tokyo, Japan) whenever applicable, swept-source optical coherence tomography (SS-OCT); DRI OCT Triton machine version 10

Statistical analysis
Data were collected, revised, coded, and entered into the Statistical Package for Social Science (IBM SPSS) version 23. The quantitative data were presented as mean, standard deviations, and ranges when parametric and median, and inter-quartile range (IQR) when data was found non-parametric. In addition, qualitative variables were presented as numbers and percentages. The comparison between two independent groups with quantitative data and nonparametric distribution was done by using the Mann-Whitney test. The comparison between two paired groups regarding quantitative data and nonparametric distribution was done by using the Wilcoxon Rank test. Spearman correlation coefficients were used to assess the correlation between two quantitative parameters in the same group. The confidence interval was set to 95% and the margin of error accepted was set to 5%. Thus, the p-value was considered significant at a level of P-value < 0.05.

Case presentation Case no. 1
A 19-year-old male patient presented to our clinic complaining of a marked drop of vision in his left eye following gazing into a laser pointer. His BCVA was 0.1. Fundus examination revealed a large neurosensory detachment in the macula with submacular hemorrhage (SMH) and hard exudates. SS-OCT revealed a sub-foveal hyperreflective amorphous lesion above the retinal pigment epithelium (RPE) consistent with SMH seen in the color photo. The lesion had an overlying SRF. SS-OCTA of the outer retina revealed a hyperintense signal characteristic of an active neovascular network. The patient received a single IVA injection. SS-OCT post-injection revealed restoration of the foveal contour with persistent organized SRH. SS-OCTA revealed a complete resolution of the previously noted hyperintense signal. His BCVA improved

Case no. 2
A 16-year-old female patient who is a known case of MFC presented to our clinic with complaints of decreased vision in the right eye. Her BCVA was 0.1. There were no signs of activity of MFC. Fundus examination revealed a submacular yellowish-white elevated lesion with a meniscus of SRH and a surrounding larger area of neurosensory detachment. SS-OCT of the right eye revealed diffuse macular thickening (spongy edema), a sub-foveal hyperreflective amorphous lesion, neurosensory detachment, and overlying SRF. SS-OCTA of the outer retina revealed a hyperintense signal characteristic of an active neovascular network. The patient received 3 consecutive IVA injections separated by 4 weeks. Eventually, SS-OCT revealed resolution of the previously noted spongy edema, neurosensory detachment, and SRF though with a persistent dome-shaped hyperreflective lesion that was consistent with macular scarring in the color photo. SS-OCTA revealed a marked reduction in the size and vascularity of the CNV. Her BCVA improved to 0.32 and remained stable throughout 6 months of follow-up after the last IVA injection Fig. 2.

Case no. 3
A 33-year-old female patient who is a known case of Best vitelliform macular dystrophy (BVMD) presented to our clinic with complaints of decreased vision in the right eye. Her BCVA was 0.32.

Discussion
In the present study, IVA induced regression of neovascular activity with an improvement of visual acuity in all 17 eyes, p < 0.001. Thirteen eyes (76%) achieved this outcome using ≤ 3 IVA injections, of which 6 eyes (35%) required only a single injection. Several studies reported similar results for the use of IVA in cases of CNV secondary to trauma, laser-induced retinal injury, uveitis, and hereditary disorders. Diafas et al [9] reported a complete resolution of CNV secondary to laser pointer injury using a single IVA injection. They had no recurrences over 38 months of follow-up. Keles et al [10] reported a complete resolution of CNV secondary to alexandrite laser retinal injury using 3 IVA injections. They did not have recurrence over a 1-year follow-up. Another report by Arrevola et al [11] had regression of a CNV secondary to PIC after 2 IVA injections with no recurrences throughout 2 years of follow-up. Korol et al [12] administered a loading dose (3 consecutive injections) of IVA followed by a PRN regimen in a series of 15 eyes with a CNV secondary to toxoplasma chorioretinitis. They required a mean of 1.7 injections and they reported no persistent CNV during a 1-year follow-up. The authors did not detect serious ocular or systemic side effects. Gliem et al [13] reported a case series of 15 eyes with a CNV secondary to angioid streaks due to PXE. The treatment protocol included a single injection of IVA at the outset of enrollment followed by a PRN regimen. The authors administered a mean number of 6.7 injections over 1 year. They reported stable visual acuity in 67% of eyes. At the end of the follow-up period, 33% of eyes had persistent or recurrent CNV. None of the patients enrolled in the study had serious side effects related to IVA. The INTUITION study [8] reported a series of 16 patients with idiopathic CNV. The treatment protocol included a loading dose of 3 IVA injections followed by a treat-and-extend (TER) regimen up to week 20. Thereafter, a PRN protocol was used up to week 52. The authors reported significant improvement in BCVA, reduction in central retinal thickness, and CNV area. The mean number of IVA injections at the end of the follow-up was 5.4. There were no serious side effects related to IVA injection. In congruence with the safety reports of IVA by Korol et al [12], Gliem et al [13], and the INTUITION study [8], we did not detect any ocular or systemic side effects associated with IVA injection in the present study.
Our results corroborate those of the fore-mentioned studies and support the notion that the damage induced to the RPE-Bruch's membrane complex by certain fundus disorders with secondary CNV formation is self-limiting compared to the chronic progressive pathology of nAMD [14]. The reason could be that the primary triggering factor has ceased to exist after producing localized damage to the RPE-Bruch's complex as in the case of trauma, laser injury, or resolved inflammation. Similarly, the damage sustained by the RPE-Bruch's complex could be subtle and very slowly progressing as in hereditary diseases. Whatever the reason, the VEGF load produced is possibly far less than that produced secondary to AMD, where the progressive compromise of the RPE-Bruch's membrane complex by drusen with consequent release of proangiogenic and proinflammatory cytokines leads to a perpetual release of VEGF and other angiogenic factors [14]. Therefore, it is prudent in the management of those patients to follow a reactive anti-VEGF injection protocol that is individualized for each patient per the response of the CNV to injection to avoid overtreatment and to reduce the risks associated with intraocular injections. In this sense, IVA could be a better agent than bevacizumab and ranibizumab due to its stronger bondage to VEGF and thus a longer duration of action [1,4,5]. An important point of strength in the present study is that we used a multimodal imaging protocol that included a tandem of FFA, SS-OCT, and SS-OCTA in the diagnosis and the follow-up of the response of CNV to IVA. The rationale for using this multimodal protocol is that the classic features that are pathognomonic of CNV on FFA and OCT are either displayed in an atypical manner or overlap with the signs of the primary disease in cases of secondary CNV. For instance, the vitelliform material in BVMD has the same optical properties as the fibrovascular tissue of CNV on OCT. Similarly, leakage on FFA is a common feature between inflammatory chorioretinal diseases and CNV. Consequently, these pathologies could be indistinguishable when using conventional FFA and OCT. In this sense, SS-OCTA is decisive in establishing the presence of CNV by displaying the hyperintense signal that is However, both factors might have been dictated by the relatively low prevalence of CNV secondary to the pathologies discussed.

Conclusion
The customized IVA injection regimen is effective in inducing long-term regression of CNV secondary to trauma, laser maculopathy, uveitis, and hereditary disorders and in improving visual function. This approach avoids overtreatment and has a high safety profile. Multimodal imaging is fundamental in establishing the diagnosis of CNV. SS-OCTA is conclusive in the early detection of subtle CNV and in monitoring regression of the CNV during followup, particularly whenever OCT and FFA reveal equivocal results.